Neuropathic pain caused by trauma and surgery is a significant health problem. Since chronic neuropathic pain often is inadequately relieved by conventional analgesics, its treatment represents an important unmet clinical need. The major objective of this grant renewal is to determine the role of groups II and III metabotropic glutamate receptor (mGluR) subtypes in the regulation of spinal synaptic transmission and nociception in neuropathic pain. Increased glutamatergic input to spinal dorsal horn neurons is critically involved in development of neuropathic pain. However, little is known about the contribution of groups II and mGluR subtypes in the spinal cord to central sensitization and neuropathic pain. The specific aims of this project are to: (1) determine the mGluR subtypes that mediate the therapeutic effect of spinally administered group II and III mGluR agonists on allodynia and hyperalgesia and hyperactivity of dorsal horn neurons in neuropathic pain;(2) examine the temporal changes in groups II and III mGluR subtypes in the spinal dorsal horn after nerve injury and define the contribution of individual groups II and III mGluR subtypes in the spinal cord to neuropathic pain symptoms;(3) determine the role of groups II and III mGluR subtypes in the spinal cord in the regulation of glutamatergic and GABAergic transmission in neuropathic pain;and (4) identify the distinct signaling mechanisms of the presynaptic actions of groups II and III mGluRs in the feedback control of synaptic glutamate release to spinal dorsal horn neurons. Our overall hypothesis is that nerve injury decreases presynaptic groups II and III mGluRs in the spinal dorsal horn and that downregulation of these mGluRs contributes to increased glutamatergic input and hypersensitivity of spinal dorsal horn neurons in neuropathic pain. To test this hypothesis, we will use many state-of-the-art approaches, including electrophysiological recording of dorsal horn neurons in vivo, whole-cell patch-clamp recordings in spinal cord slices, measurements of mGluR expression, spinal mGluR gene silencing with siRNAs, and behavioral assessment of nociception. The proposed studies are important for a better understanding of the cellular and molecular mechanisms of spinal synaptic plasticity in neuropathic pain. The novel information gained also will provide a rationale for development of new subtype-specific groups II and III mGluR agonists to treat patients with intractable neuropathic pain.